In utero exposure to cigarette chemicals induces sex-specific disruption of one-carbon metabolism and DNA methylation in the human fetal liver

Abstract

BackgroundMaternal smoking is one of the most important modifiable risk factors for low birthweight, which is strongly associated with increased cardiometabolic disease risk in adulthood. Maternal smoking reduces the levels of the methyl donor vitamin B12 and is associated with altered DNA methylation at birth. Altered DNA methylation may be an important mechanism underlying increased disease susceptibility; however, the extent to which this can be induced in the developing fetus is unknown.MethodsIn this retrospective study, we measured concentrations of cobalt, vitamin B12, and mRNA transcripts encoding key enzymes in the 1-carbon cycle in 55 fetal human livers obtained from 11 to 21 weeks of gestation elective terminations and matched for gestation and maternal smoking. DNA methylation was measured at critical regions known to be susceptible to the in utero environment. Homocysteine concentrations were analyzed in plasma from 60 fetuses.ResultsIn addition to identifying baseline sex differences, we found that maternal smoking was associated with sex-specific alterations of fetal liver vitamin B12, plasma homocysteine and expression of enzymes in the 1-carbon cycle in fetal liver. In the majority of the measured parameters which showed a sex difference, maternal smoking reduced the magnitude of that difference. Maternal smoking also altered DNA methylation at the imprinted gene IGF2 and the glucocorticoid receptor (GR/NR3C1).ConclusionsOur unique data strengthen studies linking in utero exposures to altered DNA methylation by showing, for the first time, that such changes are present in fetal life and in a key metabolic target tissue, human fetal liver. Furthermore, these data propose a novel mechanism by which such changes are induced, namely through alterations in methyl donor availability and changes in 1-carbon metabolism.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0251-x) contains supplementary material, which is available to authorized users.

Placental 5-methylcytosine and 5-hydroxymethylcytosine patterns associate with size at birth

“…An effect of maternal smoking on IGF2 expression in placenta would not be surprising since we have recently shown that maternal smoking reduces IGF2 expression in human fetal liver. 37 Maternally expressed genes including CDKN1C act to restrict fetal and placental growth, 38 and our data showing decreasing CDKN1C expression with increased birth weight are consistent with this and with a previous study reporting increased expression in association with SGA. 10 Maternal smoking had no effect on CDKN1C expression, suggesting that any effects of smoke exposure are gene-specific, again consistent with our previous data in human fetal liver.…”

“…10 Maternal smoking had no effect on CDKN1C expression, suggesting that any effects of smoke exposure are gene-specific, again consistent with our previous data in human fetal liver. 37 5mC enrichment at IGF2 DMR0 and KvDMR was positively related to birth weight SD score. However the consequences of this are unclear, since there was no correlation between DNA methylation at these regions and IGF2 and CDKN1C mRNA levels.…”

SExual Epigenetic Dimorphism in The Human Placenta: Implications for Susceptibility During The Prenatal Period

“…For example, placentas derived from pregnancies of males and females display variation in the abundance and type of glucocorticoid transporter proteins, the expression of hormones and the production of immune-related proteins including cytokines [12,[19][20][21]. In addition, sex-based differences in response to prenatal stressors have been observed at the levels of the placental proteome, transcriptome and epigenome [3,7,14,20,[22][23][24][25][26][27]. Thus, the sexually dimorphic nature of the placenta could influence variation in toxicant transport and accumulation, hormone levels and immune future science group Research Article Martin, Smeester, Bommarito et al response experienced by the fetus.…”

Cobalamin Concentrations in Fetal Liver Show Gender Differences: A Result from Using a High-Pressure Liquid Chromatography–Inductively Coupled Plasma Mass Spectrometry as an Ultratrace Cobalt Speciation Method

“…The reason why there 410 is a gender difference is still unclear and how the C1 metabolism of the fetus is 411 influenced when the mother smokes has been discussed elsewhere. 11 The data also 412 …”

“…Cbl concentrations above the detection limits. The first results of the study has been 398 published partly by Drake et al 11 with regards to lifestyle influence on the Cbl 399 concentration in the fetal livers without describing the analytical method in detail. 400…”